This revised collaborative R01 application is designed to identify susceptibility genes for bipolar disorder (BD) by testing single nucleotide polymorphisms (SNPs) across chromosomal regions previously linked to BD. Our proposal is an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large treatment study involving approximately 5000 affected individuals. The sample will consist of consenting probands from STEP-BD (n = 1780), consenting family members, and a sample of unrelated controls. Because of its unprecedented size and longitudinal nature, STEP-BD provides a unique opportunity for the genetic dissection of BD. We will conduct the study in stages as follows: 1) perform a meta-analysis of available genome scans of BD to identify regions most likely to harbor susceptibility loci, 2) use pooled genotyping methods to test SNPs under these linkage peaks in a Screening Sample of 550 cases and 550 unrelated controls, 3) follow-up positive associations in a Family-Based Sample of 1361 nuclear families using family-based and haplotype analyses with a more focused and dense SNP map, and 4) perform secondary analyses to evaluate epitasis among associated loci and examine phenotypic subtypes. This proposal combines the advantages of systematic phenotyping and statistical power offered by the STEP-BD cohort together with innovative molecular and statistical genetic methods to permit rigorous evaluation of chromosomal regions most strongly implicated by prior linkage studies. The feasibility of this proposal has been further enhanced since the previous submission because NIMH will be separately funding the collection of DNA and phenotypic data from STEP-BD cases to establish a repository for the scientific community. Moreover, Dr. Nimgaonkar and Dr. Smoller (PIs for the current proposal) will be co-directing this effort on behalf of the STEP-BD study. Identification of liability genes would represent a major advance in understanding the pathophysiology of BD, and might guide the development of more effective and targeted treatments. An important dividend of this large study will be the expansion of the repository to include DNA data on relatives and on an independent sample of controls, thus facilitating future genetic studies.